Cocaine receptor binding ligands

ABSTRACT

A class of binding ligands for cocaine receptors and other receptors in the brain. Specifically, a novel family of compounds shows high binding specificity and activity, and, in a radiolabeled form, can be used to bind to these receptors, for biochemical assays and imaging techniques. Such imaging is useful for determining effective doses of new drug candidates in human populations. In addition, the high specificity, slow onset and long duration of the action of these compounds at the receptors makes them particularly well suited for therapeutic uses, for example as substitute medication for psychostimulant abuse. Some of these compounds may be useful in treating Parkinson&#39;s Disease or depression, by virtue of their inhibitory properties at monoamine transporters.

CONTINUING APPLICATION INFORMATION

This application is a Continuation of U.S. application Ser. No.10/279,851, filed on Oct. 25, 2002, pending, which is a Continuation ofU.S. application Ser. No. 08/706,263, filed on Sep. 4, 1996, now U.S.Pat. No. 6,531,483, which is a Continuation-In-Part of U.S. applicationSer. No. 08/506,541, filed on Jul. 24, 1995, abandoned, which is aContinuation-in-Part of U.S. application Ser. No. 08/436,970, filed onMay 8, 1995, now U.S. Pat. No. 5,736,123 and a Continuation-in-Part ofU.S. application Ser. No. 08/164,576, filed on Dec. 10, 1993, now U.S.Pat. No. 5,496,953. U.S. application Ser. No. 08/436,970 is aContinuation-in-Part of U.S. application Ser. No. 08/164,576, which is aContinuation-in-Part of U.S. application Ser. No. 07/972,472, filed onMar. 23, 1993, now U.S. Pat. No. 5,413,779, and a which is aContinuation-in-part of U.S. application Ser. No. 07/792,648, filed onNov. 15, 1991, now U.S. Pat. No. 5,380,848 and a Continuation-in-part ofInternational Application No. PCT/US91/05553, filed on Aug. 9, 1991,which is a Continuation-in-part of U.S. application Ser. No. 07/564,755filed on Aug. 9, 1990, now U.S. Pat. No. 5,128,118, all of which areincorporated herein by reference.

FIELD OF THE INVENTION

This invention is directed to a class of binding ligands for cocainereceptors and other receptors in the brain. Specifically, a novel familyof compounds shows high binding specificity and activity, and, in aradiolabeled form, can be used to bind to these receptors, forbiochemical assays and imaging techniques. Such imaging is useful fordetermining effective doses of new drug candidates in human populations.In addition, the high specificity, slow onset and long duration of theaction of these compounds at the receptors makes them particularly wellsuited for therapeutic uses, for example as substitute medication forpsychostimulant abuse. Some of these compounds may be useful in treatingParkinson's Disease or depression, by virtue of their inhibitoryproperties at monoamine transporters.

DISCLOSURE OF PARENT APPLICATIONS

This application claims priority, inter alia, from of U.S. patentapplication Ser. No. 07/972,472 filed Mar. 23, 1993, now U.S. Pat. No.5,413,779, the entirety of which is incorporated by reference. Thisapplication also claims priority from U.S. patent application Ser. No.07/564,755, now U.S. Pat. No. 5,128,118, and U.S. PCT ApplicationPCT/US91/05553 (the U.S. National Phase of which is U.S. Pat. No.07/972,472), filed Aug. 9, 1991, both applications being incorporatedherein by reference. In U.S. patent application Ser. No. 07/564,755,there is disclosure of a family of compounds exhibiting particularlyhigh specificity and affinity for cocaine receptors and otherneurotransmitter receptors in the brain of the formula:

Where the broken line represents an optional chemical bond and thesubstituents at 2 and 3 may be at any position;

The iodo substituent may be at o, m, p, or multisubstituted;

-   R₁=CH₃, CH₂CH═CH₂, (CH₂)_(n)C₆H₅ n=1–4;-   R₂=CH₃, C₂H₅, CH₃(CH₂)₃, (CH₃)₂CH, C₆H₅, C₆H₅CH₂, C₆H₅(CH₂)₂;-   X=pharmacologically acceptable anion    Sites of specific interest included cocaine receptors associated    with dopamine (DA) transporter sites.

Subsequently, in the U.S. PCT Application from which priority isclaimed, and which is incorporated herein by reference, the values forR₁ and R₂ were expanded, such that R₁ may be an alkyl of 1–7 carbonatoms, CH₂CR₃═CR₄R₅ wherein R₃–R₅ are each, independently C₁₋₆ alkyl, orphenyl compounds of the formula C₆H₅(CH₂)_(y) wherein y=1–6. The PCTfiling also reveals the affinity of these compounds for cocainereceptors associated with serotonin (5-hydroxytryptamine, 5-HT)transporters, and confirms, for the first time, that the in vitrobinding reported in the earlier-filed application, is confirmed in invivo testing. Specific disclosure for a variety of applications,including using the compounds in both PET and SPECT scanning, whereineither the iodine substituent, or one of the carbon groups isradioactive (I-123, 125 or 131 and C11) thus providing methods forscanning for the presence of specific cocaine receptors. Such scanningprocesses may be used to determine physiological conditions associatedwith dopamine and serotonin reuptabe inhibitors, which lead tobehavioral and neurodegenerative disorders/diseases. Such disordersinclude depression, bipolar disorder, eating disorders, obesity,attention deficit disorder, panic attacks and disorders,obsessive-compulsive disorder, Parkinson's Disease, and cocaine,nicotine and alcohol addiction. These compounds, in addition to beingused in treatment of these disorders, may be used to examine in generalthe density and distribution of specific cocaine receptors in variousparts of the brain and/or body, to determine the efficacy ofneurological treatments aimed at halting or reversing the degenerationof specific nerves in the brain, and for screening drugs, such asantidepressant drugs.

The affinity and specificity of these compounds, as reported in theapplications incorporated, is surprisingly high, and compared with priorart compounds, such as [³H]WIN 35,428, the novel compounds of theseapplications exhibit extremely low IC₅₀ values for binding inhibition.

In U.S. patent application Ser. No. 08/506,541, filed Jul. 24, 1995,also incorporated herein by reference in its entirety, a family ofcompounds was disclosed, having the formula:

Wherein

-   R₁ is hydrogen, C₁₋₅ alkyl-   R_(a) is phenyl, C₁₋₆ alkyl, C₁₋₆ alkyl-substituted phenyl-   R_(b) is C₁₋₆ alkyl, phenyl, C₁₋₆ alkyl substituted phenyl and-   Z is phenyl or naphtyl bearing 1–3 substituents selected from the    group consisting of F, Cl, I, and C₁₋₆ alkyl.

These compounds exhibit unusually high affinity and specificity forbinding to receptors for the dopamine transporter site, as well as theserotonin transporter site, based on inhibition of [³H]paroxetinebinding. This high affinity makes certain of these compoundsparticularly well suited for use as therapeutic agents, as well as forimaging agents for dopamine and serotonin transporters.

SUMMARY OF THE INVENTION

Accordingly, one object of this invention is to provide novel compoundswhich bind to cocaine receptors.

Another object of the invention is to provide novel 3-(substitutedphenyl)-2-(substituted)tropane analogs which bind to cocaine receptors.

Still another object of the invention is to provide 3-(substitutedphenyl)-2-(substituted)tropane analogs which bind preferentially to thedopamine transporter.

Yet another object of the invention is to provide 3-(substitutedphenyl)-2-(substituted)tropane analogs which bind preferentially to theserotonin transporter.

Another object of the invention is to provide a compound of the formula

wherein R is CH₃, C₂H₅, CH₂CH₂CH₃, or CH(CH₃)₂, R₁ is CH₃, CH₂C₆H₅,(CH₂)₂C₆H₅, (CH₂)₃C₆H₅, or

wherein X is H, OCH₃, or Cl and Y is H, OCH₃, or Cl, and n=1–8.

Another object of the invention is to provide compounds having thefollowing formulas:

wherein

-   R₁=hydrogen, C₁₋₅ alkyl,-   X=H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₆ alkynyl,    halogen, amino, acylamido, and-   Z=H, I, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₁, CONH₂, CO₂R₁, C₁₋₆ alkyl,    NR₄R₅, NHCOR₅, NHCO₂R₆,-   R_(b) is C₁₋₆ alkyl, phenyl, C₁₋₆ alkyl substituted phenyl

A further object of the invention is to provide a method for treatingpsychostimulant abuse, by administering to a patient in need of suchtreatment a pharmaceutically effective amount of a 3-(substitutedphenyl)-2-(substituted)tropane analog.

A still further object of the invention is to provide method forinhibiting the action of a psychostimulant, by administering to apatient in need of such treatment a psychostimulant-inhibiting amount ofa 3-(substituted phenyl)-2-(substituted)tropane analog.

Still another object of the invention is to provide a method forinhibiting neurotransmitter re-uptake by administering to a patient inneed of such treatment a neurotransmitter transporter-inhibiting amountof a 3-(substituted phenyl)-2-(substituted)tropane analog.

Another object of the invention is to provide a method for treatingneurodegenerative disorders, by administering to a patient in need ofsuch treatment a pharmaceutically effective amount of a 3-(substitutedphenyl)-2-(substituted)tropane analog.

Still another object of the invention is to provide a method fortreating depression, by administering to a patient in need of suchtreatment a pharmaceutically effective amount of a 3-(substitutedphenyl)-2-(substituted)tropane analog.

Briefly, the invention pertains to the discovery that certain cocaineanalogs are particularly well suited for therapeutic use asneurochemical agents. These particular cocaine analogs, in modulatingneurotransmitter actions, may also be useful for modulating the actionsof pyschostimulant drugs, for modulating endocrine function, formodulating motor function, and for modulating complex behaviors.

With the foregoing and other objects, advantages and features of theinvention that will become here in after apparent, the nature of theinvention may be more clearly understood by reference to the followingdetailed description of the preferred embodiments of the invention andto the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 depicts the scheme for converting 3-(substitutedphenyl)-2-tropane carboxylic acid (tropane acid) to 2-substitutedtetrazoles, oxazoles, oxadiazoles, thiazoles, thiadiazoles andbenzothiazole.

FIG. 2 depicts the scheme in which the carboxamide obtained from thetropane acid was treated to obtain nitrites and tetrazoles.

FIG. 3 depicts the scheme used to prepare 3-substituted isoxazoles.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes novel compounds having the followingformula:

The compounds of this invention can be prepared according to thesynthesis methods described in the parent applications. Alternativesynthesis for related compounds will be apparent to those of ordinaryskill in the art. Particular synthesis schemes are exemplified in U.S.Pat. No. 5,444,070, which is incorporated herein in its entirety.Additional schemes follow hereinbelow.

Preparation of 3β-(Substituted phenyl)tropane-2β-heterocyclic Analogues

Chemistry

The known 3β-(substituted phenyl)-2β-tropane carboxylic acid (tropaneacid) (Carroll et al., J. Med. Chem. 35:1813–1817 (1992)) served as thestarting material for the synthesis of 2β-substituted tetrazoles,oxazoles, oxadiazoles, thiazoles, thiadiazoles and benzothiazole asshown in FIG. 1.

The tropane acid was refluxed with N-acetyl and benzoic hydrazide inphosphorous oxychloride to obtain the corresponding 5-substituted1,3,4-oxadiazoles (Afanasiadi et al., Chem. Heterocyclic Compd. 397–400(1995)). N-benzoyl hydrazide amide obtained by the reaction of the acidchloride of tropane acid with N-benzoic hydrazide was cyclized withLawesson's reagent (El-Barbary et al., Acta Chimica Scandinavica 597–601(1980)) in refluxing THF to the 5-substituted 1,3,4-thiadiazoles. TheN-phenylacyl carboxamide obtained from tropane acid and2-aminoacetophenone was cyclized by refluxing the amide in phosphorousoxychloride to obtain the required 5-substituted oxazoles (Carroll etal., Med. Chem. Res. 3:468 (1993)). Cyclization of the same amide withLawesson's reagent (El-Barbary et al., 1980) in refluxing THF gave the5-substituted thiazoles respectively. The benzothiazole was obtainedwithout the cyclization step by the reaction of acid chloride obtainedfrom the appropriate tropane acid with 2-aminothiophenol.

The previously reported carboxamide (Carroll et al., 1993) obtained fromthe tropane acid was dehydrated with trifluoroacetic acid and pyridinein THF to the nitriles (Campagna et al., Tet. Letts. 22:1813–1816(1977)) as shown in FIG. 2. Cycloaddition of trimethylsilylazide to thenitrile afforded the corresponding tetrazoles (Saunders et al., Med.Chem. 33:1128–1138 (1990)).

FIG. 3 outlines the route used to prepare 3-substituted isoxazole. Theknown tropane compounds (Carroll et al., J. Med. Chem. 34:2719–2725(1991)) were treated with dilithiated methyl or phenyl acetoneoximes,obtained by the treatment of acetone or acetophenoneoxime with n-BuLi at0° C. The corresponding addition product was cyclized without isolationusing sulfuric acid at reflux temperature to furnish the requiredisoxazoles (Saunders et al., 1990).

The therapeutic effects of the present cocaine analogs can be analyzedin various ways, many of which are well known to those of skill in theart. In particular, both in vitro and in vivo assay systems may be usedfor the screening of potential drugs which act as agonists orantagonists at cocaine receptors, or drugs which are effective tomodulate neurotransmitter level or activity, in particular by binding toa transporter of that neurotransmitter.

The compounds of the invention may be prepared and labeled with anydetectable moiety, in particular a radioactive element, and may then beintroduced into a tissue or cellular sample. After the labeled materialor its binding partner(s) has had an opportunity to react with siteswithin the sample, the location and concentration of binding of thecompound may be examined by known techniques, which may vary with thenature of the label attached.

Illustrative in vitro assays for binding are described in Boja et alAnn. NY Acad. Sci. 654:282–291 (1992), which is incorporated herein byreference in its entirety. A particularly preferred in vitro assayinvolves the ability of a compound in question to displace the bindingof a known labelled compound to binding sites in a tissue sample,isolated membranes or synaptosomes. Alternatively, the compounds may beanalyzed by their ability to inhibit reuptake of a labelledneurotransmitter in a sample, in particular, in synaptosomes.

The compound or its binding partner(s) can also be labeled with anydetectable moiety, but are preferably labelled with a radioactiveelement. The radioactive label can be detected by any of the currentlyavailable counting procedures, including the imaging procedures detailedin the disclosures of the parent applications. The preferred isotope maybe selected from ³H, ¹¹C, ¹⁴C, ¹¹C, ³²P, ³⁵S, ³⁶Cl, ⁵¹Cr, ⁵⁷Co, ⁵⁸Co,⁵⁹Fe, ⁹⁰Y, ¹²⁵I, ¹³¹I, and ¹⁸⁶Re.c,

As noted in the parent disclosures, the binding of the labelledcompounds may be analyzed by various imaging techniques, includingpositron emission tomography (PET), single photon emission computedtomography (SPECT), autoradiogram, and the like. Such imaging techniquesare useful for determining effective doses of new drug candidates. Byperforming in vivo competition studies, it is possible to use brainimaging studies to determine the oral doses of new drug candidates,which produce significant receptor occupancy in the brain. In vivodisplacement studies which determine in vivo IC50's which in turnreflect doses that occupy receptors in vivo are described in Cline et al((1992) Synapse 12:37–46). In addition to its uses in determining invivo potency/occupancy, these same brain imaging methods can be used todetermine rate of entry of compounds into the brain (Stathis et al(1995) Psychopharmacology 119:376–384) and duration of action (Volkow etal (1995) Synapse 19:206–211).

The binding of the compounds of the invention may be at any locationwhere a receptor for a particular psychostimulant is present, and morespecifically, any location where a dopamine or serotonin transporter ispresent. Such locations are in general any area comprising a part of thedopamine or serotonin pathway, in particular at synapses. Examples oflocations known to be associated with dopamine transport include thecerebral cortex, hypothalamus, substantia nigra, nucleus accumbens,arcuate nucleus, anterior periventricular nuclei, median eminence andamygdala. Examples of locations known to be associated with serotonininclude the striatum, cerebral cortex, hypothalamus, Raphe nuclei,pre-optic area and suprachiasmatic nucleus.

By “psychostimulant” is meant any compounds whose abuse is dependentupon mesolimbic and mesocortical dopaminergic pathways. In particular,psychostimulant relates to cocaine. However, the compounds of theinvention may also be used to treat abuse of compounds not traditionallyclassified as “psychostimulants,” but which act at a dopamine orserotonin transporter. Such abused compounds include ethanol andnicotine.

For in vivo studies, the compounds of the invention may be prepared inpharmaceutical compositions, with a suitable carrier and at a strengtheffective for administration by various means to a patient experiencingan adverse medical condition associated with cocaine receptor binding orneurotransmitter release and reuptake, for the treatment thereof. Theaction of the compounds may be analyzed by the imaging methods notedabove, and also by behavioral studies. In particular, the pharmaceuticaleffects of the compounds of the invention may be reflected in locomotoractivity, including the induction of ipsilateral rotation, stereotypedsniffing and the “swim test”, in schedule-controlled operant behavior(i.e., response for food or shock termination) or drugself-administration. In general, maximal behavioral effects are seen atnear complete occupancy of transporter sites. Such protocols aredescribed in Boja et al (1992), Balster et al Drug and AlcoholDependence 29:145–151 (1991), Cline et al Pharm. Exp. Ther.260:1174–1179 (1992), and Cline et al Behavioral Pharmacology 3:113–116(1992), which are hereby incorporated herein by reference in theirentireties.

A variety of administrative techniques may be utilized, among them oralor parenteral techniques such as subcutaneous, intravenous,intraperitoneal, intracerebral and intracerebroventricular injections,catheterizations and the like. Average quantities of the compounds mayvary in accordance with the binding properties of the compound (i.e.,affinity, onset and duration of binding) and in particular should bebased upon the recommendations and prescription of a qualified physicianor veterinarian.

The compounds of the invention preferably have a long duration ofaction, which is important to facilitate dosing schedules. In rats, thepresent compounds have a 7–10 fold longer duration of action thancocaine (Fleckenstein et al, “Highly potent cocaine analogs causelong-lasting increases in locomotor activity,” Eur. J. Pharmacol., inpress, which is incorporated herein by reference in its entirety). Inaddition, the present compounds also preferably have a slow rate ofentry into the brain, which is important in decreasing the potential forabuse (Stathis et al, supra, which is incorporated herein by referencein its entirety). The present compounds enter the brain more slowly thancocaine.

The therapeutic compositions useful in practicing the therapeuticmethods of this invention may include, in admixture, a pharmaceuticallyacceptable excipient (carrier) and one or more of the compounds of theinvention, as described herein as an active ingredient.

The preparation of therapeutic compositions which contain suchneuroactive compounds as active ingredients is well understood in theart. Such compositions may be prepared for oral adminstration, or asinjectables, either as liquid solutions or suspensions, however, solidforms suitable for solution in, or suspension in, liquid prior toinjection can also be prepared. The preparation can also be emulsified.The active therapeutic ingredient is often mixed with excipients whichare pharmaceutically acceptable and compatible with the activeingredient. Suitable excipients are, for example, water, saline,dextrose, glycerol, ethanol, or the like and combinations thereof. Inaddition, if desired, the composition can contain minor amounts ofauxiliary substances such as wetting or emulsifying agents, and pHbuffering agents which enhance the effectiveness of the activeingredient. The compounds of the invention can be formulated into thetherapeutic composition as neutralized pharmaceutically acceptable saltforms.

The therapeutic compositions are conventionally administered orally, byunit dose, for example. The term “unit dose” when used in reference to atherapeutic composition of the present invention refers to physicallydiscrete units suitable as unitary dosage for humans, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect in association with the requireddiluent; i.e., carrier, or vehicle.

The compositions are administered in a manner compatible with the dosageformulation, and in a therapeutically effective amount. The quantity tobe administered depends on the subject to be treated, the presence ofother agonists and antagonists in the subject's system, and degree ofbinding or inhibition of binding desired. Precise amounts of activeingredient required to be administered depend on the judgment of thepractitioner and are peculiar to each individual. However, suitabledosages may range from about 0.01 to about 1000, preferably about 0.25to about 500, and more preferably 10 to 50 milligrams of activeingredient per kilogram body weight of individual per day and depend onthe route of administration. However, the exact dosage must bedetermined by factoring in rate of degradation in the stomach,absorption from the stomach, other medications administered, etc.Suitable regimes for administration and are also variable, but aretypified by an initial administration followed by repeated doses at oneor more hour intervals by a subsequent injection or otheradministration. Alternatively, continuous intravenous infusionsufficient to maintain appropriate concentrations in the blood arecontemplated.

The compounds of the present invention may be administered for theiractivities as surrogate agonist medications for cocaine, nicotine,alcohol, amphetamine and other psychostimulant abuse. Because of theirfavorable binding characteristics to transporters of neurotransmitters,they may be used for inhibiting the uptake of dopamine, norepinephrine,serotonin and other monoamines. The compounds of the present inventionmay find use as antipsychotics, antidepressants, local anesthetics,anti-Parkinsonian agents, anti-obesity drugs, drugs useful in thetreatment of bipolar disorder, eating disorders, obesity, attentiondeficit disorder, panic attacks and disorder, obsessive-compulsivedisorder, sexual dysfunction, as anticholinergic agents and as sigmareceptor drugs.

The compounds of the invention may also be useful in treatingneurodegenerative disorders, in particular for treating Parkinson'sDisease, but also may be useful in the treatment of cocaine, nicotineand alcohol addiction.

The preferred compounds of the present invention are derived from theseries of compounds designated RTI-4229. The physical properties of someof these compounds are given in Table I.

TABLE I Physical Properties of 2β-substituted Hetrocyclic Analogs of3β-(4-Substituted-phenyl) Tropane and Cocaine Molecular code nameCompound Formulae^(a) mp ° C. [α]D (c) MeOH Yield % RTI-188C₂₂H₂₃Cl₂N₃O^(e) 160–162 +84.59 (0.36) 42 RTI-195 C₂₃H₂₆ClN₃O^(e)175–178 +97.22 (0.25) 40 RTI-194 C₁₈H₂₄ClN₃O^(d) 146 (dec) −43.05 (0.15)58 RTI-200 C₂₂H₂₃Cl₂N₃S^(e) 165–170 −42.81 (0.16) 58 RTI-199C₂₃H₂₆ClN₃S^(d) 180–185 −33.50 (0.20) 58 RTI-189 C₂₇H₂₉ClN₂O₇ ^(b,e) 126(dec) +101.43 (0.21) 49 RTI-178 C₂₈H₃₂N₂O₇ ^(b,f) 175–181 −104.04 (0.60)72 RTI-219 C₂₃H₂₄ClN₂S^(f) 228–230 +27.43 (0.11) 30 RTI-202C₂₁H₂₂Cl₂N₂S^(c) 140–150 (dec) −172.49 (0.28) 41 RTI-161 C₁₅H₁₈Cl₂N₂^(e) >220 (dec) −71.00 (0.50) 77 RTI-158 C₁₆H₂₁ClN₂ 270 (dec) −76.40(0.50) 67 RTI-163 C₁₅H₁₈ClN₅ ^(e) 296–300 −124.94 (0.39) 33 RTI-157C₁₆H₂₃Cl₂N₅ ^(c) >212 (dec) −110.97 (0.16) 88 RTI-165 C₁₈H₂₂Cl₂N₂O 235(dec) −102.89 (0.46) 46 RTI-171 C_(l9)H₂₅ClN₂O 277 −107.28 (0.71) 62RTI-180 C₁₈H₂₂ClN₂O^(c) >235 (dec) −94.57 (0.39) 49 RTI-177C₂₃H₂₄Cl₂N₂O^(c) 287 −97.50 (0.28) 50 RTI-176 C₂₄H₂₇ClN₂O 270–295 (dec)−102.22 (0.68) 77 RTI-181 C₂₃H₂₄ClN₂O^(d) >2679 (dec) −91.11 (0.43) 56RTI-184 C₁₉H₂₃ClN₂O₃ ^(d) 117–121 −53.60 (0.25) 82 RTI-185 C₂₄H₂₅ClN₂O₃205 −56.71 (0.43) 68 ^(a)HGI Salt; ^(b)Tartrate Salt ^(c)0.25 mol water;^(d)0.5 mol water; ^(e)0.75 mol water; ^(f)1 mol water.Many of the preferred compounds of the invention fall within the broadclass of compounds described by the formula:

Wherein Y=CH₂R₃, CO₂R₂, CONRR¹

-   R₁=hydrogen, C₁₋₅ alkyl,-   R₂=hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₆ alkynyl,    halogen, amine, CH₂C₆H₅, (CH₂)₂C₆H₅, (CH₂)₃C₆H₅ or

-   R₃=OH, hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, Cl, Br,    I, CN, NH₂, NHC₁₋₆ alkyl, NC₁₋₆ alkyl, OCOC₁₋₆ alkyl, OCOC₁₋₃    alkylaryl,-   A=S, O or N-   X=H, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₆ alkynyl,    halogen, amino, acylamido, C₂H₅, CH₂CH₃CH₃, CH(CH₃)₂,-   Z=H, I, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₁, CONH₂, CO₂R₁, C₁₋₆ alkyl,    NR₄R₅, NHCOR₅, NHCO₂R₆, and-   Q¹ and Q² may be the same or different and ═H, OCH₃, or Cl,    wherein R₄–R₆ are each C₁₋₆ alkyl, R and R¹ are independently H,    C₁₋₆ alkyl, C₁₋₆ alkene, C₁₋₆ alkyne, phenyl, phenyl substituted    with 1–3 of C₁₋₆ alkyl, alkene, alkyl or alkoxy, C₁₋₆ alkoxy,    phenoxy, amine, amine substituted with 1–2 of C₁₋₆ alkyl, alkene,    alkyne, alkoxy or phenyl or phenoxy or R and R¹ may combine to form    heterocyclic structure including pyrrolidinyl, piperidinyl and    morpholino moieties, unsubstituted or substituted with 1–2 C₁₋₆    alkyl, alkene, alkyne or alkoxy groups.

The present inventors have surprisingly found that certain of theRTI-4229 series of compounds are particularly potent pharmaceuticalagents in accordance with the present invention.

Preferred compounds of the RTI-4229 series include the following:RTI-4229-31, 32, 51, 55, 83, 96, 97, 98, 101, 105, 108, 110, 111, 112,116, 121, 122, 127, 132, 139, 140, 142, 145, 146, 147, 150, 153, 178,188, 189, 190, 191, 193, 195, 199, 200, 203, 204, 205, 206, 219, 230,239, 240, 241, 242, 251, 252, 274, 277, 278, 279, 280, 281, 282, 283,286, 287, 296, 304, 305, 307, 309, 318, and 330. The chemical structuresof these compounds, along with their IC₅₀ values for inhbition ofradioligand binding are given below. DA is dopamine, 5-HT is5-hydroxytryptamine (serotonin), and NE is norepinephrine, DA=[³H]WIN35, 428; 5-HT=[³H] paroxetine and NE_(N)=[³H] nisofetine:

RTI-4229-31 DA5-HTNE_(N) 1.12 ± 0.1 44.5 ± 1.34 37 ± 2.1

RTI-4229-32 DA5-HTNE_(N) 1.71 ± 0.31240 ± 27   60 ± 0.53

RTI-4229-51 DA5-HTNE_(N) 1.69 ± 0.2310.6 ± 0.2437.4 ± 5.2 

RTI-4229-55 DA5-HTNE_(N) 1.26 ± 0.044.24 ± 0.3436 ± 3 

RTI-4229-83 DA5-HTNE_(N) 55 ±  228.4 ± 3.834,027.87 ± 380.70  

RTI-4229-96 DA5-HTNE_(N) 2.95 ± 0.58 76 ± 2.8 520 ± 10.4

RTI-4229-97 DA5-HTNE_(N) 3.91 ± 0.59181 ± 14 282 ± 30 

RTI-4229-98 DA5-HTNE_(N) 0.69 ± 0.2  0.36 ± 0.04710.97 ±0.88 

RTI-4229-101 DA5-HTNE_(N)  2.2 ± 0.19 26 ± 3.2±

RTI-4229-105 DA5-HTNE_(N) 1.60 ± 0.05143 ± 25 127.2 ± 5.9 

RTI-4229-108 DA5-HTNE_(N) 2.64 ± 0.31 98 ± 8.7129.3 ± 15  

RTI-4229-110 DA5-HTNE_(N) 0.62 ± 0.094.13 ± 0.625.45 ± 0.21

RTI-4229-111 DA5-HTNE_(N) 0.79 ± 0.083.13 ± 0.3617.96 ± 0.85 

RTI-4229-112 DA5-HTNE_(N) 0.82 ± 0.0510.5 ± 0.4136.2 ± 1.02

RTI-4229-116 DA5-HTNE_(N)  33 ± 3.91,227 ± 176  967.55 ± 26.25  

RTI-4229-121 DA5-HTNE_(N) 0.43 ± 0.0566.84 ± 6.53 285 ± 7.6 

RTI-4229-122 DA5-HTNE_(N) 1.50 ± 0.35184.38 ± 21.91 3,791 ± 149  

RTI-4229-127 DA5-HTNE_(N) 19 ± 1 4,499 ± 557  3,444 ± 44  

RTI-4229-132 DA5-HTNE_(N) 3.48 ± 0.11208 ± 18 137.3 ± 10.5 

RTI-4229-139 DA5-HTNE_(N) 1.67 ± 0.13 85 ± 9.356.9 ± 2.6 

RTI-4229-140 DA5-HTNE_(N) 101 ± 16 5,701 ± 721  2,076 ± 285  

RTI-4229-142 DA5-HTNE_(N) 4.39 ± 0.2068.59 ± 2.02 18.78 ± 0.68 

RTI-4229-145 DA5-HTNE_(N) 9.60 ± 0.422,932 ± 181  1,478 ± 96  

RTI-4229-146 DA5-HTNE_(N) 2.05 ± 0.2398 ± 10144 ± 3 

RTI-4229-147 DA5-HTNE_(N) 1.38 ± 0.0312,393.99 ± 1207.03  3,949 ± 72  

RTI-4229-150 DA5-HTNE_(N) 3.74 ± 0.522,019 ± 133  4,478 ± 322  

RTI-4229-153 DA5-HTNE_(N) 1.06 ± 0.123.59 ± 0.27132 ± 5 

RTI-4229-173 DA5-HTNE_(N) 49.9 ± 7.3 8.13 ± 0.30122 ± 12 

RTI-4229-178 DA5-HTNE_(N) 35.4 ± 1.741,698.77 ± 166.68   677 ± 67.5

RTI-4229-188 DA5-HTNE_(N) 12.56 ± 1.03 3,303.76 ± 195.85   929 ± 88.1

RTI-4229-189 DA5-HTNE_(N) 19.71 ± 1.98 1,116.18 ± 107.148  496 ± 42.1

RTI-4229-190 DA5-HTNE_(N) 0.96 ± 0.10168 ± 1.8  235 ± 8.39

RTI-4229-191 DA5-HTNE_(N) 0.61 ± 0.0815.5 ± 0.72101.7 ± 10.5 

RTI-4229-193 DA5-HTNE_(N) 1.68 ± 0.141,066.38 ± 109.12   644 ± 27.7

RTI-4229-195 DA5-HTNE_(N) 47.48 ± 4.76 22,310.9 ± 822.83 1,310 ± 36.7  

RTI-4229-199 DA5-HTNE_(N) 35.88 ± 3.40 51,459.7 ± 4,513.10 24,320.8 ±3,822.61

RTI-4229-200 DA5-HTNE_(N) 15.29 ± 2.43 18,416.5 ± 1,508.794,142.08 ±466.07  

RTI-4229-203 DA5-HTNE_(N) 9.37 ± 0.522,153 ± 143.18  2,743.73 ± 140.92  

RTI-4229-204 DA5-HTNE_(N) 3.91 ± 0.233,772.17 ± 383.64  4,782.70 ±487.10  

RTI-4229-205 DA5-HTNE_(N) 8.19 ± 0.905,237.30 ± 453.397 2,136.62 ±208.52  

RTI-4229-229 DA5-HTNE_(N) 5.71 ± 0.3610,341.5 ± 76.11  8,563 ± 824  

RTI-4229-230 DA5-HTNE_(N) 1.28 ± 0.1757.41 ± 5.04  141 ± 16.1

RTI-4229-239 DA5-HTNE_(N) 0.61 ± 0.07114.3 ± 3.69 35.6 ± 2.57

RTI-4229-240 DA5-HTNE_(N) 1.38 ± 0.0338.4 ± 2.3184.5 ± 3.09

RTI-4229-241 DA5-HTNE_(N) 1.02 ± 0.06618.5 ± 28   124 ± 3.58

RTI-4229-242 DA5-HTNE_(N) 7.67 ± 0.31226.54 ± 27.37 510.1 ± 51.4 

RTI-4229-251 DA5-HTNE_(N) 1.93 ± 0.1410.1 ± 1.1  114 ± 13.1

RTI-4229-252 DA5-HTNE_(N) 2.56 ± 0.2235.2 ± 2.45124.6 ± 8.3 

RTI-4229-274 DA5-HTNE_(N) 3.96 ± 0.2 5.62 ± 0.2 14.4 ± 1.3 

RTI-4229-277 DA5-HTNE_(N) 5.94 ± 0.612,909.71 ± 255.41  5,695.38 ±214.72  

RTI-4229-278 DA5-HTNE_(N) 8.14 ± 0.732,146.50 ± 138.71  4,095.01 ±413.45  

RTI-4229-279 DA5-HTNE_(N) 5.98 ± 0.481.06 ± 0.1074.3 ± 3.8 

RTI-4229-280 DA5-HTNE_(N) 3.12 ± 0.396.81 ± 0.41484.13 ± 51.6 

RTI-4229-281 BIH-141-7 DA5-HTNE_(N) 2.37 ± 0.2815.69 ± 1.5 820.5 ± 45.8 

RTI-4229-282 BIH-141-2 DA5-HTNE_(N) 68.53 ± 7.08 70.38 ± 4.13 3921.58 ±130  

RTI-4229-283 BIH-141-12 DA5-HTNE_(N) 14.35 ± 0.3 3.13 ± 0.163125 ± 333 

RTI-4229-286 DA5-HTNE_(N) 20.7 ± 0.575062 ± 485 1231 ± 91 

RTI-4229-287 DA5-HTNE_(N) 325 ± 20 1686 ± 140 17,819 ± 440  

RTI-4229-296 BIH-141-1 DA5-HTNE_(N) 5.29 ± 0.5311.39 ± 0.28 1592.23 ±93.4  

RTI-4229-304 BIH-141-11 DA5-HTNE_(N) 15.04 ± 1.2 7.09 ± 0.712799 ± 300 

RTI-4229-305 BIH-141-18 DA5-HTNE_(N) 1.24 ± 0.111.59 ± 0.2 21.8 ± 1.0 

RTI-4229-307 BIH-141-15 DA5-HTNE_(N) 6.11 ± 0.673.16 ± 0.33115.8 ± 5.1 

RTI-4229-309 BIH-141-17 DA5-HTNE_(N) 1.73 ± 0.052.25 ± 0.1714.9 ± 1.18

RTI-4229-318 DA5-HTNE_(N) 0.51 ± 0.030.80 ± 0.0621.1 ± 1.0 

RTI-4229-330 DA5-HTNE_(N) 310.2 ± 21  15.1 ± 0.97±

Particularly preferred compounds include RTI-4229-77, 87, 113, 114, 117,119, 120, 124, 125, 126, 130, 141, 143, 144, 151, 152, 154, 165, 171,173, 176, 177, 180, 181, 194, 202, 295, 298, 319, 334, 335, 336, 337,338, 345, 346, 347, 348, 352 and 353. The chemical structures of thesecompounds are given below:

Particularly preferred compounds include RTI-4229-77, 87, 113, 114, 117,119, 120, 124, 125, 126, 130, 141, 143, 144, 151, 152, 154, 165, 171,173, 176, 177, 180, 181, 194, 202, 295, 298, 319, 334, 335, 336, 337,338, 345, 346, 347, 348, 352 and 353. The chemical structures of thesecompounds are given below:

RTI-4229-77 DA5-HTNE_(N) 2.51 ± 0.25±2,246.86 ± 238.99  

RTI-4229-87 DA5-HTNE_(N) 204 ± 29 29.391 ± 2.324 35.782 ± 6.245 

RTI-4229-113 DA5-HTNE_(N) 1.98 ± 0.052.336 ± 176  2.955 ± 223  

RTI-4229-114 DA5-HTNE_(N) 1.40 ± 0.131.404 ± 7.1 778 ± 21 

RTI-4229-117 DA5-HTNE_(N) 6.45 ± 0.856.090 ± 488  1.926 ± 38  

RTI-4229-119 DA5-HTNE_(N) 167 ± 1340.615 ± 9.416 6.985 ± 635  

RTI-4229-120 DA5-HTNE_(N) 3.26 ± 0.0624,471 ± 1,515 5,833 ± 373  

RTI-4229-124 DA5-HTNE_(N) 1,028 ± 65  33,085 ± 5,434 70,993 ± 3,563 

RTI-4229-125 DA5-HTNE_(N) 4.05 ± 0.572,584 ± 799  363 ± 36 

RTI-4229-126 DA5-HTNE_(N) 100 ± 6.3¹²3.824 ± 418  7,876 ± 551  

RTI-4229-130 DA5-HTNE_(N) 1.62 ± 0.02195 ± 4.8 245 ± 13 

RTI-4229-141 DA5-HTNE_(N) 1.81 ± 0.19337 ± 43 835 ± 7.5 

RTI-4229-143 DA5-HTNE_(N)  4.1 ± 0.22404 ± 56 4,069 ± 177  

RTI-4229-144 DA5-HTNE_(N) 3.44 ± 0.38106 ± 10 1.825 ± 166   RTI-4229-151DA5-HTNE_(N) 2.33 ± 0.261.074 ± 125  60 ± 2  RTI-4229-152 DA5-HTNE_(N)494 ± 37 1.995 ± 109  22.689 ± 1.957 

RTI-4229-154 DA5-HTNE_(N)  6.0 ± 0.553,460 ± 245  135 ± 13 

RTI-4229-165 DA5-HTNE_(N) 0.59 ± 0.04572 ± 58 161 ± 12 

RTI-4229-171 DA5-HTNE_(N) 0.93 ± 0.093,818.25 ± 346.14  254 ± 31 

RTI-4229-176 DA5-HTNE_(N) 1.58 ± 0.025,109.72 ± 187.101  398 ± 17.6

RTI-4229-177 DA5-HTNE_(N) 1.28 ± 0.182,418.21 ± 135.68  504 ± 29 

RTI-4229-180 DA5-HTNE_(N) 0.73 ± 0.0436.35 ± 4.99 67.9 ± 5.25

RTI-4229-181 DA5-HTNE_(N) 2.57 ± 0.14100 ± 9.0 868 ± 95 

RTI-4229-194 DA5-HTNE_(N) 4.45 ± 0.124,884.47 ± 155.42   253 ± 18.9

RTI-4229-202 DA5-HTNE_(N) 1.37 ± 0.141,118.85 ± 120.00  402.8 ± 29.5 

DA5-HTNE_(N) 21.31 ± 0.87 2.96 ± 0.041349 ± 105 

RTI-4229-298 BIH-141-4 DA5-HTNE_(N)  3.7 ± 0.1646.8 ± 5.8 346.6 ± 25  

RTI-4229-319 DA5-HTNE_(N)  1.1 ± 0.0911.4 ± 1.3 70.2 ± 6.28

RTI-4229-334 DA5-HTNE_(N) 0.50 ± 0.033086 ± 153  120 ± 10.4

RTI-4229-335 DA5-HTNE_(N) 1.19 ± 0.122318 ± 153  954 ± 97.3

RTI-4229-336 DA5-HTNE_(N) 4.09 ± 0.445741 ± 421 1714 ± 38.5  

RTI-4229-337 DA5-HTNE_(N) 7.31 ± 0.6136.842 ± 3616  6321 ± 703 

RTI-4229-338 DA5-HTNE_(N) 1104.2 ± 54.6 7.41 ± 0.553366 ± 584 

RTI-4229-345 DA5-HTNE_(N) 6.42 ± 0.46>76,000 ±       5290.4 ± 448.99

RTI-4229-346 DA5-HTNE_(N) 1.57 ± 0.105880.4 ± 179  762.01 ± 37.8 

RTI-4229-347 DA5-HTNE_(N) 1.86 ± 0.097256.95 ± 210    918.4 ± 108.34

RTI-4229-348 DA5-HTNE_(N) 28.2 ± 1.9 34.674 ± 3954  2667.2 ± 6267.3

RTI-4229-352 DA5-HTNE_(N) 2.86 ± 0.2164.9 ± 1.9752.4 ± 4.9 

RTI-4229-353 DA5-HTNE_(N) 330.54 ± 17.12 0.69 ± 0.07148.4 ± 9.15 

It should be noted that compound RTI-353 is a highly potent compound atthe serotonin site, and is selective relative to the dopamine andnorepinephrine sites. This compound is particularly useful as anantidepressant, and as an imaging agent for serotonin transporters.

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

EXAMPLES

All certified grade reagents or solvents were purchased from AldrichChemical Co. or Fluka Chemical Co. All reagents were normally usedwithout further purification. When anhydrous conditions were required,solvents were distilled and dried by standard techniques immediatelyprior to use.

All air and moisture sensitive reactions were conducted under aprepurified nitrogen atmosphere in flame-dried glassware, previouslydried at 150° C. Anhydrous solvents were transferred using conventionalsyringe or steel canula techniques under an inert atmosphere. Removal ofsolvents in vacuo was done on a Buchi rotavapor rotary evaporatoroperated at water aspirator pressure.

¹H NMR and ¹³C NMR spectra were recorded at 250 Mhz on a Bruker AM250spectrometer. Optical rotations were recorded on at the Sodium D line ona Rudolph Research Autopol III polarimeter (1 dm cell). Melting pointwas recorded on a Uni-melt Thomas Hoover capillary melting pointapparatus in open capillary tubes and were uncorrected. Elementalanalysis were performed by Atlantic Microlab, Inc., Norcross, Ga.

Reaction products were purified by flash column chromatography usingsilica gel (mesh size 230–400) purchased from VWR Scientific. Thin layerchromatography (TLC) was performed on Whatman 254 nm fluorescent silicagel 60A (1×3 inches, 250 [μL thickness]) precoated TLC plates using thesolvent systems indicated. Developed chromatograms were evaluated under254 nm UV light or with iodine.

Example 1 General Procedure for the Preparation of Amides

To a solution of 1 mmol of 3β-(4-Chlorophenyl)-tropane-2β-carboxylicacid or 3β-(4-Methylphenyl)-tropane-2β-carboxylic acid in 5 ml ofmethylene chloride was added dropwise with stirring under nitrogen 2.0eqoxalyl chloride (2 M solution in methylene chloride). The resultingsolution was stirred at room temperature for an hour after evolution ofgas has ceased. The solvent was removed in vacuo at room temperature andthen at high vacuum to remove residual traces of oxalyl chloride. Theresulting residue of acid chloride was suspended in 5 ml methylenechloride under nitrogen at 0° C., and 2.0 eq of the amine hydrochloridecontaining 4.0 eq of triethylamine, or 2.5 eq of the amine free base wasadded. The mixture was stirred at room temperature overnight. Aqueous 3NNaOH (5 ml) was added to basify the reaction mixture, the organic layerwas separated and the aqueous layer extracted with 3×10 ml chloroform.The combined organic layers were dried (Na₂SO₄), filtered and thesolvent removed in vacuo to give crude product. The crude was purifiedby flash column chromatography or crystallization.

Example 2 3β-(4-Chlorophenyl)-2β-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropaneHydrochloride (RTI-188)

To a solution of 0.59 g (2 mmol) of3β-(4-Chlorophenyl)-tropane-2β-carboxylic acid (chloro acid) in 2 ml OfPOCl₃ was added 0.31 g (2.2 mmol) of N-benzoic hydrazide and refluxedunder nitrogen for 2 hours. The reaction mixture was cooled, poured intoice and rendered basic to pH 7–8 using concentrated NH₄OH. To the icecold aqueous layer was added 10 ml brine and extracted thrice with 10 mlmethylene chloride. The organic layers were combined dried (NaSO₄),filtered, and the solvent removed in vacuo to give 0.9 g of cruderesidue. Purification of the residue by flash column chromatography [50%(ether/triethylamine 9:1) in hexanel] gave 0.33 g (42%) of pureoxadiazole (RTI-188) which was recrystallized from ether/petroleumether: ¹H NMR (CDCl₃) 1.81 (m, 3H), 2.18 (s, 3H), 2.26 (m, 2H), 2.66 (m,1H), 3.33 (m, 2H), 3.51 (m, 2H), 7.16 (m, 4H) 7.45 (m, 3H), 7.86 (m,2H); IR (CHCl₃) 2950, 1550, 1490, 1450, 1340, 1090 cm⁻¹; [α]_(D)−106.25° (c=0.08, CHCl₃).

The oxadiazole was converted into hydrochloride salt: ¹H NMR (MeOD) 2.08(m, 1H), 2.57 (m, 5H), 3.0 (s, 3H), 4.01 (m, 2H), 4.15 (m, 1H), 4.39 (m,1H), 7.24 (m, 4H), 7.52 (m, 5H): mp 160–162° C.; Anal calcd forC₂₂H₂₃Cl₂N₃O.0.75H₂O; C=61.47; H=5.74, N=9.78; Cl=16.50; found C=61.47,H=5.73, N=9.76; Cl=16.56; [α]_(D) +84.59° (c=0.36, CH₃OH).

Further elution gave as a second fraction 0.1 g (13%) of white solidwhich was characterized to be3β-(4-Chlorophenyl)-2β-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane: ¹H NMR(CDCl₃) 1.76 (m, 3H), 2.06 (s, 3H), 2.45 (s, 3H), 3.36 (m, 2H), 3.51 (m,1H), 3.65 (m, 1H), 7.21 (m, 4H), 7.47 (m, 3H) 7.91 (m, 2H); mp 170–171°C.; Anal calcd for C₂₂H₂₂CIN₃O; C=69.55; H=5.84, N=11.06; Cl=9.33; foundC=69.49, H=5.85, N=11.01; Cl=9.41; [α]_(D) +33.06° (c=0.18, CHCl₃)

Example 3 3β-(4-Methylphenyl)-2β-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropaneHydrochloride (RTI-195)

Reaction of 0.65 g (2.5 mmol) of3β-(4-Methylphenyl)-tropane-2β-carboxylic acid (Methyl acid) asdescribed above for RTI-188 gave after work-up and purification by flashcolumn chromatography [(50% (ether/triethylamine 9:1) in hexane] 0.36 g(40%) of pure oxadiazole (RTI-195) which was recrystallized fromether/petroleum ether: ¹H NMR (CDCl₃) 1.83 (m, 3H), 2.18 (s, 3H), 2.21(s, 3H), 2.3 (m, 2H), 2.67 (m, 1H), 3.33 (m, 1H), 3.41 (m, 1H), 3.53 (m,1H), 3.61 (m, 1H) 7.0 (m, 2H), 7.13 (m, 2H), 7.44 (m, 3H), 7.86 (m, 2H);IR (CHCL₃) 2990, 1545, 1505, 1440, 1350. cm⁻¹; [α]_(D) −163.92° (c=0.2,CHCl₃).

The oxadiazole was converted into hydrochloride salt: ¹H NMR (MeOD) 2.05(m, 1H), 2.21 (s, 3H), 2.51 (m, 5H), 2.99 (s, 3H), 3.86 (m, 1H), 3.95(m, 1H), 4.14 (m, 1H), 4.35 (m, 1H), 7.02 (m, 4H) 7.53 (m, 5H); mp175–178° C.; Anal calcd for C₂₃H₂₆CIN₃O.0.75H₂O; C=67.47; H=6.77,N=10.26; Cl=8.66; found C=67.58, H=6.79, N=10.34; Cl=8.78; [α]_(D)+97.22° (c=0.25, CH₃OH).

Further elution gave as a second fraction 0.18 g (20%) of solid whichwas characterized to be3β-(4-Methylphenyl)-2α-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane which wasrecrystallized from ether/petroleum ether: ¹H NMR (CDCl₃) 1.77 (m, 2H),2.0 (m, 4H), 2.25 (s, 3H), 2.47 (s, 3H), 3.33 (m, 2H), 3.51 (m, 1H),3.69 (d of d, J=2.6, 12 Hz, 1H), 6.91 (m, 2H) 7.03 (m, 2H). 7.45 (m,2H), 7.45 (m, 3H), 7.89 (m, 2H); IR (CHCL₃) 3020, 1540, 1510, 1415,1250, 1215. cm⁻¹; Anal calcd for C₂₃H₂₅N₃O; C=76.85; H=7.01, N=11.69;found C=76.60, H=7.12, N=11.55; [α]_(D) +40.73° (c=0.28, CHCl₃)

Example 4 3β-(4-Methylphenyl)-2β-(5-methyl-1,3,4-oxadiazol-2-yl)-tropaneHydrochloride (RTI-194)

Reaction of 0.65 g (2.5 mmol) of methyl acid as described above forRTI-195 using 0.21 g (2.75 mmol) of N-acetic hydrazide gave afterwork-up and Purification by flash column chromatography [(75%(ether/triethylamine 9:1) in hexane] 0.29 g (39%) of pure oxadiazole(RTI-194) which was recrystallized from ether/petroleum ether: ¹H NMR(CDCl₃) 1.75 (m, 3H), 2.18 (s, 3H), 2.22 (s, 3H), 2.25 (m, 2H), 2.35 (s,3H), 2.56 (m, 1H), 3.24 (m, 1H), 3.4 (m, 2H), 3.47 (m, 1H) 7.0 (m, 4H);¹³C NMR (CDCl₃) 11.06, 20.9, 25.08, 26.32, 34.11, 34.6, 41.83, 45.73,61.97, 66.21, 127.11, 128.85, 135.85, 138.19, 162.5, 167.44; IR (CHCL₃)2950, 1590, 1510, 1450, 1350, 1215 cm ⁻¹; [α]_(D) −108.47° (c=0.14,CHCl₃).

The-oxadiazole was converted into hydrochloride salt: ¹H NMR (MeOD) 1.99(m, 1H), 2.23 (s, 3H), 2.27 (s, 3H), 2.47 (m, 5H), 2.94 (s, 3H), 3.72(m, 1H), 3.79 (m, 1H), 4.10 (m, 1H), 4.23 (m, 1H), 7.05 (m, 4H); mp 146°C. (dec); Anal calcd for C₁₈H₂₄CIN₃O.0.5H₂O ; C=63.06; H=7.35, N=12.26;Cl=10.34; found C=63.21, H=7.40, N=12.07; Cl=10.27; [α]_(D) −43.05°(c=0.15, CH₃OH).

Example 53β-(4-Chlorophenyl)-2β-(5-phenyl-1,3,4-thiadiazol-2-yl)-tropaneHydrochloride (RTI-200)

Reaction of 0.59 g (2 mmol) of 3β-(4-Chlorophenyl)tropane-2β-carboxylicacid as described above for the preparation of amides gave afterpurification of the crude by crystallizing from ethyl acetate/ether 0.52g (66%) of pureN-[3β-(4-Chlorophenyl)-tropane-2β-carboxylic]-N′-benzoylhydrazide: ¹HNMR (CDCl₃) δ 1.76 (m, 3H), 2.24 (m, 2H), 2.41 (s, 3H), 2.51 (m, 1H),2.68 (m, 1H), 3.18 (m, 1H), 3.44 (m, 2H), 7.22 (m, 4H), 7.46 (m, 3H),7.78 (m, 2H), 9.02 (br s, 1H), 12.97 (br s, 1H); IR (CHCl₃) 3385, 3035,3000, 1620, 1570, 1485, 1450, 1215 cm⁻¹.

A solution of 0.4 g (1 mmol) ofN-[3β-(4-Chlorophenyl)-tropane-2β-carboxylic]-N′-benzoyl-hydrazide and0.8 g (2 mmol) of Lawesson's reagent in 10 ml toluene was refluxed for 4h under nitrogen. The reaction mixture was cooled and solvent removed invacuo to give a yellow residue. To the residue was added 3 g of silicagel and 10 ml of methylene chloride, the resulting slurry was mixedproperly and the solvent removed in vacuo. The crude compoundimpregnated on silica gel was loaded on a column and purified by flashcolumn chromatography [50% ether/triethylamine(9:1) in hexane] to obtain0.23 g (58%) of pure thiadiazole (RTI-200) which was further purified byrecrystallizing from ether: ¹H NMR (CDCl₃) δ 1.75 (m, 3H), 2.20 (m, 3H),2.32 (s, 3H), 3.30 (m, 3H), 3.78 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H),7.43 (m, 3H), 7.97 (m, 2H); ¹³C NMR 25.55, 25.88, 34.60, 36.09, 41.55,49.73, 61.48, 65.33, 127.59, 128.28, 128.78, 128.88, 130.37, 130.88,132.19, 139.27, 168-29, 169.56; IR (CCl₄) 2940, 1490, 1460, 1340, 1245,1100, 1010 cm⁻¹

The thiadiazole was converted into hydrochloride salt: ¹H NMR (MeOD) δ2.06 (m, 1H), 2.53 (m, 5H), 2.97 (s, 3H), 3.92 (m, 1H), 4.17 (m, 2H),4.39 (m, 1H), 7.11 (m, 2H), 7.26 (m, 2H), 7.51 (m, 3H), 7.79 (m, 2H); mp165–170° C.; Anal calcd for C₂₂H₂₃Cl₂N₃S.0.75H₂O; C=59.26, H=5.54,N9.42, Cl=15.90; S=7.19. found C=59.27, H=5.52, N=9.40, Cl=15.99; S7.09; [α]_(D) −42.81° (c=0.16, MeOH).

Further elution gave 0.08 g (21%) as a second fraction which wascharacterized to be3β-(4-chlorophenyl)-2α-(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane.

Example 63β-(4-Methylphenyl)-2β-(5-phenyl-1,3,4-thiadiazol-2-yl)-tropaneHydrochloride (RTI-199)

Reaction of 0.65 g (2.5 mmol) of3β-(4-Methylphenyl)-tropane-2β-carboxylic acid as described above forpreparation of amides gave after work up and purification by flashcolumn chromatography [(50% CMA-80 in methylene chloride)] 0.48 g (51%)pure N-[3β-(4-Methylphenyl) Tropane-2β-carboxylic]-N′-benzoyl-hydrazidewhich was further purified by recrystallizing from ether/pet ether: ¹HNMR (CDCl₃) δ 1.75 (m, 3H), 2.20 (m, 2H), 2.27 (s, 3H), 2.42 (s, 3H),2.51 (m, 1H), 2.67 (m, 1H), 3.18 (m, 1H), 3.47 (m, 2H), 7.11 (m, 4H),7.48 (m, 3H), 7.81 (m, 2H), 9.06 (br s, 1H), 13.09 (br s, 1H); IR(CHCl₃) 3385, 3045, 1625, 1570, 1460, 1420, 1100 cm⁻¹;

Reaction of 0.29 g (0.75 mmol) ofN-[3β-(4-Methylphenyl)-tropane-2β-carboxylic]-N′-benzoyl-hydrazide asdescribed above for RTI-200 gave after work and purification by flashchromatography [40% ether/triethylamine(9:1) in hexane] 0.16 g (58%) ofpure thiadiazole (RTI-199): ¹H NMR (CDCl₃) δ 1.70 (m, 1H), 1.88 (m, 2H),2.20 (s, 3H), 2.23 (m, 2H), 2.21 (s, 3H), 2.38 (m, 1H), 3.21 (m, 1H),3.32 (m, 1H), 3.39 (m, 1H), 3.78 (m, 1H), 6.81 (m, 2H), 6.92 (m, 2H),7.43 (m, 3H), 7.97 (m, 2H); ¹³C NMR 20.98, 25.65, 25.95, 34.79, 36.25,41.65, 50.05, 61.68, 65.49, 127.32, 127.65, 128.89, 128.95, 130.29,131.11, 135.94, 137.68, 168.83, 169.45; IR (CCl₄) 2935, 1510, 1450,1250, 1120, 1100, 1060 cm⁻¹

The thiadiazole was converted into hydrochloride salt; ¹H NMR (MeOD) δ1.95 (m, 1H), 2.17 (s, 3H), 2.41 (m, 5H), 2.89 (s, 3H), 3.76 (m, 1H),4.05 (m, 2H), 4.30 (m, 1H), 4.22 (m, 1H), 6.89 (m, 2H), 6.99 (m, 2H),7.39 (m, 3H), 7.67 (m, 2H); mp 180–185° C.; Anal calcd forC₂₃H₂₆CIN₃S.H₂O; C=65.62, H=6.46, N=9.98, Cl=18.42; S=7.62. foundC=65.57, H=6.63, N=9.91, Cl=18.24; S=7.55; [α]_(D) −33.5° (c=0.2, MeOH)

Further elution gave 0.04 g (15%) of a second fraction which wascharacterized to be3β-(4-Methylphenyl)-2α(5-phenyl-1,3,4-oxadiazol-2-yl)-tropane.

Example 7 3β-(4-Chlorophenyl)-2β-(5-phenyl-oxazol-2-yl)-tropane TartrateRTI-189)

Reaction of 0.73 g (2.5 mmol) of 3β-(4-Chlorophenyl)-tropane-2βcarboxylic acid as described above for the preparation of amides gaveafter purification by flash column chromatography (15% CMA 80 inmethylene chloride) 0.8 g (81%) of pure3β-(4-Chlorophenyl)-tropane-2β-N-(phenyacyl) carboxamide: ¹H NMR (CDCl₃)δ 1.71 (m, 3H), 2.19 (m, 2H), 2.39 (s, 3H), 2.46 (m, 1H), 2.58 (m, 1H),3.13 (m, 1H), 3.43 (m, 2H), 4.74 (m, 2H), 7.13 (m, 4H), 7.49 (m, 2H),7.59 (m, 1H), 7.96 (m, 2H), 10.57 (br s, 1H); IR (CHCl₃) 3135, 3010,2930, 1695, 1650, 1590, 1530, 1485, 1450, 1355, 1220 cm⁻¹.

A solution of 0.725 g (1.83 mmol) of3β-(4-Chlorophenyl)-tropane-2β-N(phenyacyl)carboxamide in 6 ml POCl₃ washeated at 125° C. under nitrogen for 2 hours. The reaction mixture wascooled and poured into ice and rendered basic to pH 7–8 usingconcentrated NH₄OH. To the ice cold aqueous layer was added 10 ml brineand extracted thrice with 10 ml methylene chloride. The organic layerswere combined dried (NaSO₄), filtered, and the solvent removed in vacuoto 0.63 g crude oxazole. Purification of the crude by flash columnchromatography [(40% (ether/triethylamine 9:1) in hexane] gave 0.34 g(49%) of pure oxazole (RTI-189) which was further purified byrecrystallizing from ether/petroleum ether: ¹H NMR (CDCl₃) 1.79 (m, 3H),2.22 (s, 3H), 2.27 (m, 2H), 2.66 (m, 1H), 3.27 (m, 1H), 3.40 (m, 2H),3.53 (m, 1H), 7.11 (s, 1H), 7.16 (s, 4H) 7.31 (m, 5H); IR (CHCl₃) 2950,1540, 1490, 1445, 1350, 1120, 1090 CM⁻¹; [α]_(D) −70.37° (c=0.19,CHCl₃).

The oxazole was converted into tartrate salt: ¹H NMR (MeOD) 2.14 (m,1H), 2.54 (m, 5H), 2.96 (s, 3H), 3.75 (m, 2H), 4.12 (m, 1H), 4.25 (m,1H), 4.41 (s, 2H), 7.05 (m, 2H), 7.29 (m, 7H), 7.45 (s, 1H), 7.43 (s,1H); mp 126° C. (dec); Anal calcd for C₂₇H₂₉CIN₂O₇.0.75H₂0; C=59.78;H=5.67, N=5.16; Cl=6.54; found C=59.78, H=5.58, N=4.93; Cl=6.31; [α]_(D)+101.43° (c=0.21, CH₃OH).

Example 8 3β-(4-Methylphenyl)-2β-(5-phenyl-oxazol-2-yl)-tropane Tartrate(RTI-178)

Reaction of 0.52 g (2 mmol) of 3β-(4-Methylphenyl)-tropane-2β-carboxylicacid as described above for preparation of amides gave after work up andpurification by flash column chromatography (15% CMA in methylenechloride) 0.54 g (72%) of pure3β-(4-Methylphenyl)-tropane-2β-N-(phenyacyl) carboxamide: ¹H NMR (CDCl₃)δ 1.73 (m, 3H), 2.14 (m, 2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.47 (m, 1H),2.59 (m, 1H), 3.14 (m, 1H), 3.42 (m, 2H), 4.74 (m, 2H), 7.05 (m, 4H),7.48 (m, 2H), 7.59 (m, 2H), 7.97 (m, 2H), 10.62 (br s, 1H); IR (CHCl₃)3155, 3005, 2930, 1690, 1650, 1520, 1450, 1355, 1215 cm⁻¹

Reaction of 0.5 g (1.33 mmol) of3β-(4-Methylphenyl)-tropane-2β-N-(phenyacyl)carboxamide as describedabove for RTI-189 gave after workup and purification by flash columnchromatography [(40% (ether/triethylamine 9:1) in hexane] 0.1 g (31%)RTI-158 as a first fraction. Further elution gave 0.19 g (42%) of pureoxazole RTI-178: ¹H NMR (CDCl₃) 1.8 (m, 3H), 2.18 (m, 2H), 2.21 (s, 3H),2.22 (s, 3H), 2.67 (m, 1H), 3.28 (m, 1H), 3.42 (m, 2H), 3.53 (m, I H),6.98 (m, 2H), 7.11 (m, 3H), 7.30 (m, 5H).

The oxazole was crystallized as the tartrate salt: ¹H NMR (MeOD) 1.99(m, 1H), 2.19 (s, 3H), 2.54 (m, 5H), 2.95 (s, 3H), 3.74 (m, 2H), 4.13(m, 1H), 4.26 (m, 1H), 4.4 (s, 2H), 6.91 (m, 2H), 7.0 (m, 2H), 7.25 (m,2H), 7.33 (m, 3H), 7.43 (s, 1H); mp 175–181 C; Anal calcd forC₂₈H₃₂N₂O₇.1H₂O ; C=63.87; H=6.51, N=5.32; found C=64.21, H=6.40,N=5.19; [α]_(D) −104.04° (c=0.6, CH₃OH)

Example 9 3β-(4-Chlorophenyl)-2β-(5-phenylthiazol-2-yl)-tropaneHydrochloride (RTI-219)

To a solution of 0.74 g (1.86 mmol) of3β-(4-Chlorophenyl)-tropane-2β-N-(phenyacyl) carboxamide and 1.51 g(7.45 mmol) of Lawesson's reagent in 18 ml of toluene was refluxed underN₂ for 5 hours. The reaction mixture was cooled and solvent removed invacuo to give crude residue. To the residue was added 3 g of silica geland 10 ml of methylene chloride, the resulting slurry was mixed properlyand the solvent removed in vacuo. The crude compound impregnated onsilica gel was loaded on a column and purified by flash columnchromatography [(40% (ether/triethylamine 9:1) in hexane] to give 0.21 g(30%) of pure thiazole RTI-219: ¹H NMR (CDCl₃) 1.61 (m, 1H), 1.82 (m,2H), 2.22 (m, 2H), 2.34 (s, 3H), 2.39 (m, 1H), 3.28 (m, 2H), 3.39 (m,1H), 3.49 (m, 1H), 6.8 (m, 2H) 7.07 (m, 2H). 7.32 (m, 3H), 7.57 (m, 2H),7.60 (s, 1H); ¹³C NMR (MeOD) 25.51, 25.99, 35.01, 36.92, 41.72, 52.97,61.58, 65.70, 126.45, 127.60, 128.13, 128.89, 129.05, 131.91, 132.43,136.11, 139.91, 140.27, 168.97; IR (CHCl₃) 2945, 1590, 1485, 1445, 1350,1125, 1090. cm⁻¹.

The thiazole was converted into hydrochloride salt: ¹H NMR (MeOD) 1.99(m, 1H), 2.51 (m, 5H), 2.93 (s, 3H), 3.79 (m, 2 H), 4.15 (m, 1H), 4.28(m, 1H), 7.02 (d, J=8.5 Hz, 2H) 7.21 (d, J=8.5 Hz, 2H), 7.39 (m, 5H),8.06 (s 1H); mp 228–230° C.; Anal calcd for C₂₃H₂₄CIN₂S.H₂O ; C=61.47,H=5.83, N=6.23, S=7.13, Cl=15.78; found C=61.61, H=5.76, N=6.20, S=7.51,Cl=15.84; [α]_(D+)27.43° (c=0.11, CH₃OH).

Example 10 3β-(4-Chlorophenyl)-2β-(benzothiazol-2-yl)-tropaneHydrochloride (RTI-202)

Reaction of 0.59 g (2 mmol) of 3β-(4-Chlorophenyl)-tropane-2β-carboxylicacid as described above for preparation of amides gave afterpurification of the crude by flash column chromatography (50% CMA-80 inmethylene chloride) 0.3 g (41%) of pure RTI-202 which was furtherpurified by recrystallizing from ether/hexane: ¹H NMR (CDCl₃) δ 1.65 (m,1H), 1.87 (m, 2H), 2.24 (m, 2H), 2.34 (s, 3H), 2.41 (m, 1H), 3.28 (m,2H), 3.40 (m, 1H), 3.62 (m, 1H), 6.8 (m, 2H), 6.81 (m, 2H), 7.29 (m,2H), 7.70 (m, 1H), 7.84 (m, 1H); ¹³C NMR (CDCl₃) δ 25.58, 26.07, 35.40,36.95, 41.56, 53.09, 61.57, 65.47, 120.95, 122.42, 124.11, 125.20,128.05, 129.03, 131.87, 136.72, 139.91, 151.33, 171.11; IR (CHCl₃) 2940,2795, 1495, 1445, 1305, 1130, 1105, 1015, 907 CM⁻¹; [α]_(D) −233.89°(c=0.09, CHCl₃).

The benzothiazole was converted into hydrochloride salt: ¹H NMR (MeOD) δ2.02 (m, 1H), 2.43 (m, 4H), 2.89 (m, 1H), 2.98 (s, 3H) 3.90 (m, 2H),4.23 (m, 1H), 4.34 (m, 1H), 7.02 (m, 2H), 7.13 (m, 2H), 7.45 (m, 2H),7.81 (m, 1H), 8.16 (m, 1H); mp 140–150° C. (dec); Anal calcd forC₂₁H₂₂Cl₂N₂S.0.75H₂O C=60.21, H=5.65, N=6.69, Cl=16.93; S=7.65: foundC=60.14, H=5.74, N=6.60, Cl=16.89; S=7.71; [α]_(D) −1 72.49° (c 0.28,MeOH).

Example 11 3β-(4-Chlorophenyl)-tropane-2β-nitrile (RTI-161)

To a solution of 0.95 g (3.5 mmol) of3β-(4-Chlorophenyl)-tropane-2β-carboxamide in 20 ml dry THF was added0.56 ml (7 mmol) pyridine. To the resulting solution at room temperaturewas added dropwise with stirring under nitrogen 0.35 ml (4.2 mmol) oftrifluoroacetic anhydride. The reaction was stirred at room temperaturefor 30 minutes, and quenched with 10 ml water. The solvent was removedunder vacuo and the residue was taken in 10 ml saturated aqueous K₂CO₃and extracted thrice with 10 ml CHCl₃. The organic layers were combinedand washed with 20 ml brine dried (NaSO₄), filtered, and the solventremoved in vacuo to give 0.26 g crude product. Purification of the crudeby flash column chromatography (10% CMA in methylene chloride) gave 0.68g (77%) of pure nitrile RTI-161 which was recrystallized from methylenechloride and hexane: ¹H NMR (CDCl₃) δ 1.70 (m, 3H), 2.22 (m, 3H), 2.35(s, 3H), 2.80 (m, 1H), 3.04 (m, 1H), 3.34 (m, 1H), 3.43 (m, 1H), 7.26(m, 4H); IR (CHCl₃) 3700, 2950, 2225, 1490, 1470, 1090, 900 cm⁻¹; mp167–173° C.; Anal calcd for C₁₅H₁₈Cl₂N_(2.)0.75H₂O; C=57.98, H=6.32N=9.02, Cl=22.82; found C=58.22, H=6.12, N=8.48, Cl=22.89; [α]_(D)−73.33° (c=0.48, MeOH).

Example 12 3β-(4-Methylphenyl)-tropane-2β-nitrile Hydrochloride(RTI-158)

Reaction of 0.26 g (1 mmol) of3β-(4-Methylphenyl)-tropane-2β-carboxamide as described above forRTI-161 gave after work up and purification 0.16 g (67%) of pure nitrile(RTI-158): ¹H NMR (CDCl₃) δ 1.68 (m, 3H), 2.18 (m, 3H), 2.32 (s, 3H),2.35 (s, 1H), 2.82 (m, 1H), 3.02 (m, 1H), 3.36 (m, 1H), 3.43 (m, 1H),7.18 (m, 4H); IR (CHCl₃) 3675, 3000, 2950, 2200, 1600, 1510, 1450, 1350,1220, 1100 cm⁻¹.

The crude product was crystallized as the HCl salt: ¹H NMR (MeOH) δ2.08–2.58 (m, 9H), 2.92 (s, 3H), 3.54 (m, 1H), 3.69 (br s, 1H), 4.12 (brs, 1H), 4.29 (m, 1H), 7.21 (m, 4H); mp 270° C. (dec.); Anal calcd forC₁₆H₂₁CIN₂; C=69.42, H=7.65; N=10.12, Cl=12.81; found C=69.31, H=7.70,N=10.12, Cl=12.81; [α]_(D) −76.40° (c=0.5, MeOH).

Example 13 3β-(4-Chlorophenyl)-tropane-2β-tetrazole (RTI-163)

To a solution of 0.13 g (0.5 mmol) of RTI-161 in 5 ml dry THF was added0.28 ml (5 mmol) azidotrimethylsilane and the mixture was placed in aPTFE-lined autoclave. The solution was heated to 150° C. for 24 hours inan oil bath. The reaction mixture was cooled and transferred using MeOH.The solvent was removed in vacuo to give a brownish residue.Purification of the crude by flash column chromatography (20%–50% CMA inmethylene chloride) gave 0.05 g (33%) of pure tetrazole (RTI-163): ¹HNMR (CDCl₃ +1 drop MeOD) δ 1.73 (m, 1H), 2.44–2.02 (m, 4H), 2.6 (m, 1H),2.68 (s, 3H), 3.33 (m, 1H), 3.65 (m, 1H), 3.73 (m, 1H), 3.97 (m, 1H),6.68 (d, J=8 Hz, 2H), 7.07 (d, J=8 Hz, 2H); mp 296–300° ; Anal calcd forC₁₅H₁ ₈CIN₅0.75H₂O ; C=56.78, H=6.19 N=22.07, Cl=11.17; found C=56.69,H=6.22, N=22.09, Cl=11.15; [α]_(D) −124.94° (c=0.39, MeOH).

Example 14 3β-(4-Methylphenyl)-tropane-2β-tetrazole Hydrochloride(RTI-157)

Reaction of 0.12 g (0.5 mmol) of RTI-158 as described above for RTI-163gave after workup and purification of the crude by flash columnchromatography (100% CMA) 0.14 g (88%) of pure tetrazole (RTI-157): ¹HNMR (CDCl₃ +1 drop MeOD) δ 1.8 (m, 1H), 2.14 (s, 3H), 2.35 (m, 5H), 2.71(s, 3H), 3.36 (m, 1H), 3.75 (m, 2H), 4.02 (m, 1H), 6.48 (d, J=8 Hz, 2H),6.82 (d, J=8 Hz, 2H).

The purified product was converted into HCl salt: ¹H NMR (MeOD) δ 2.01(m, 1H), 2.27 (s, 3H), 2.69 (m, 5H), 2.97 (s, 3H), 3.81 (m, 2H), 4.18(m, 2H), 5.5 (s, 1H), 6.76 (d, J=8 Hz, 2H), 7.02 (d, J=8 Hz, 2H); mp 212★★C (dec); Anal calcd for C₁₆H₂₃Cl₂N₅.0.25H₂O ; C=53.26, H=6.56 N=19.41;found C=53.41, H=6.50, N=19.02; [α]_(D) −110.97° (c=0.16, MeOH).

Example 15 3β-(4-Chlorophenyl)-2β-(3-methylisoxazol-5-yl)tropaneHydrochloride (RTI-165)

A solution of n-butyl lithium in hexane 5.9 ml (2.5 M. 14.6 mmol) wasadded to a stirred solution of acetone oxime 0.55 g (7.3 mmol) in dryTHF (15 ml) at 0° C. under nitrogen. After 1 hour, a solution of 1.65 g(5.62 mmol) 3β-(4-Chlorophenyl)-2β-(carbomethoxy) tropane in 10 ml drywas added dropwise with stirring at 0° C. The solution was allowed towarm to room temperature over 18 hours. The mixture was poured into astirred solution of concentrated sulfuric acid (3.2 g) in THF (15 ml)and water (4 ml) and was heated under reflux for 1 hour. The cooledsolution was made basic using saturated aqueous K₂CO₃ (10 ml) andextracted thrice with 10 ml methylene chloride. The combined organiclayers were dried (Na₂SO₄), filtered and solvent removed in vacuo togive 1.8 g of crude isoxazole. Purification of the crude residue byflash column chromatography (10% CMA in methylene chloride) gave 0.74 g(46%) of pure isoxazole RTI-165 which was further purified bycrystallization from methylene chloride/hexane: ¹H NMR (CDCl₃) δ 1.71(m, 3H), 2.10 (m, 3H), 2.18 (s, 3H), 2.24 (s, 3H), 3.20 (m, 2H), 3.32(m, 2H), 6.18 (s, 1H), 6.9 (d, J=8 Hz, 2H), 7.14 (d, J=8, Hz, 2H); IR(CCl₄) 2950, 1590, 1490, 1420, 1350, 1020, 910 cm⁻¹; mp 154–156° C.;Anal calcd for C₁₈H₂₁N₂OCL; C=68.28, H=6.68, N=8.84, Cl=11.19; foundC=68.22, H=6.69, N=8.87, Cl=11.19; [α]_(D) −125.58° (c=0.43, MeOH).

The isoxazole was crystallized as the hydrochloride salt: ¹H NMR (MeOD)δ 2.04 (s, 3H), 2.19 (m, 1H), 2.30 (m, 1H), 2.48 (m, 2H), 2.60 (m, 1H),2.70 (m, 1H), 2.90 (s, 3H), 3.68 (m, 1H), 3.81 (m, 1H), 4.04 (m, 1H),4.15 (m, 1H), 5.55 (s, 1H), 7.04 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H);mp>235° C. (dec); Anal calcd for C₁₈H₂₂Cl₂N₂O; C=61.19, H=6.28, N=7.93,Cl=20.07; found C=60.98, H=6.38, N=7.91, Cl=19.96; [α]_(D) −102.89°(c=0.46, MeOH).

Example 16 3β-(4-Methylphenyl)-2β-(3-methylisoxazol-5-yl)tropaneHydrochloride (RTI-171)

Reaction of 1.09 g (4 mmol) of3β-(4-Methylphenyl)-2β-(carbomethoxy)tropane as described above forRTI-165 gave after workup 1.21 g crude isoxazole. Purification of thecrude by flash column chromatography (15% CMA in methylene chloride)gave 0.73 g (62%) pure isoxazole (RTI-171):¹H NMR (CDCl₃) δ 1.73 (m,3H), 2.11 (m, 3H), 2.17 (s, 3H), 2.23 (s, 3H), 2.25 (s, 3H), 3.20 (m,2H), 3.32 (m, 2H), 6.13 (s, 1H), 6.97 (m, 4H); IR (CCl₄) 2935, 2785,1590, 1510, 1460, 1421, 1350, 1125,1010, 910 cm⁻¹.

The isoxazole was crystallized as the hydrochloride salt: ¹H NMR (MeOD)δ 2.01 (s, 3H), 2.24 (s, 3H), 2.32 (m, 2H), 2.42 (m, 4H), 2.81 (s, 3H),3.61 (m, 1H), 3.78 (m, 1H), 4.03 (m, 1H), 4.15 (m, 1H), 5.45 (s, 1H),6.96 (m, 4H); mp 277° C.; Anal calcd for C₁₉H₂₅CIN₂O; C=68.55, H=7.57,N=8.42, Cl=10.65; found C=68.65, H=7.62, N=8.42, Cl=10.56; [α]_(D)−107.28° (c=0.71, MEOH).

Example 17 3β-(4-Iodophenyl)-2β-(3-methylisoxazol-5-yl)tropaneHydrochloride (RTI-180)

Reaction of 0.73 g (1.9 mmol) of3β-(4-Iodophenyl)-2β-(carbomethoxy)tropane as described above forRTI-165 gave after workup 0.77 g of crude isoxazole. Purification of thecrude by flash column chromatography (5% CMA80 in methylene chloride)gave 0.37 g (49%) of pure isoxazole RTI-180: ¹H NMR (CDCl₃) δ 1.71 (m,3H), 2.12 (m, 3H), 2.18 (s, 3H), 2.24 (s, 3H), 3.17 (m, 2H), 3.33 (m,2H), 6.18 (s, 1H), 6.74 (m, 2H), 7.49 (m, 2H); IR (CHCl₃) 2940, 1600,1485, 1450, 1420, 1355 cm⁻¹.

The isoxazole was crystallized as the hydrochloride salt: ¹H NMR (MeOD)δ 2.11 (s, 3H), 2.50 (m, 6H), 2.89 (s, 3H), 3.70 (m, 1H), 3.90 (m, 1H),4.14 (m, 1H), 4.22 (m, 1H), 5.66 (s, 1H), 6.96 (m, 2H), 7.56 (m, 2H);mp>235° C. (dec); Anal calcd for C₁₈H₂₂ClIN₂O.0.25H₂O C=48.12, H=5.05,N=6.24, Cl=15.79; I=56.50; found C=47.84, H=5.05, N=6.19, Cl=15.77;I=56.46; [α]_(D) −94.57° (c=0.39, MeOH).

Example 18 3β-(4-Chlorophenyl)-2β-(3-phenylisoxazol-5-yl)tropaneHydrochloride (RTI-177)

Reaction of 1.18 g (4 mmol) of3β-(4-Chlorophenyl)-2β-(carbomethoxy)tropane as described above forRTI-165 gave after work up 1.46 g of crude isoxazole. Purification ofthe crude by flash column chromatography [20% (ether/triethylamine 9:1)in hexane] gave 0.75 g (50%) of pure isoxazole RTI-177 which was furtherpurified by crystallizing from ether/petroleum ether: ¹H NMR (CDCl₃) δ1.74 (m, 3H), 2.22 (m, 3H), 2.27 (s, 3H), 3.24 (m, 2H), 3.36 (m, 2H),6.80 (9, 1H), 6.94 (m, 2H), 7.12 (m, 2H), 7.40 (m, 3H), 7.76 (m, 2H); IR(CHCl₃) 2940, 1600, 1590, 1490, 1450, 1405, 1350 cm⁻¹.

The isoxazole was crystallized as the hydrochloride salt: ¹H NMR (MeOD)δ 2.35 (m, 6H), 2.84 (s, 3H), 3.73 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H),6.12 (s, 1H), 7.14 (m, 4H), 7.34 (m, 3H), 7.57 (m, 2H); mp 287° C.; Analcalcd for C₂₃H₂₄Cl₂IN₂O.0.25H₂O C=65.79, H=5.88, N 6.67, Cl=16.89; foundC=65.94, H=5.79, N=6.68, Cl=17.00; [α]_(D) −97.5° (c=0.28, MeOH)

Example 19 3β-(4-Methylphenyl)-2β-(3-phenylisoxazol-5-yl)tropaneHydrochloride (RTI-176)

Reaction of 1.09 g (4 mmol) of3β-(4-Methylphenyl)-2β-(carbomethoxy)tropane as described above forRTI-165 gave after work up 1.56 g of crude isoxazole. Purification ofthe crude by flash column chromatography [25% (ether/triethylamine 9:1)in hexane] gave 1.1 g (77%) of pure isoxazole RTI-176 which was furtherpurified by crystallizing from methylene chloride/hexane: ¹H NMR (CDCl₃)δ 1.76 (m, 3H), 2.23 (m, 3H), 2.24 (s, 3H), 2.27 (s, 3H), 3.23 (m, 2H),3.36 (m, 2H), 6.74 (s, 1H), 6.93 (m, 4H), 7.41 (m, 3H), 7.76 (m, 2H); IR(CCl₄) 2935, 1590, 1455, 1410, 1215 cm⁻¹

The isoxazole was crystallized as the hydrochloride salt: ¹H NMR (MeOD)δ 2.08 (m, 1H), 2.15 (s, 3H), 2.45 (m, 5H), 2.84 (s, 3H), 3.68 (m, 1H),3.88 (m, 1H), 4.07 (m, 1H), 4.22 (m, 1H), 5.97 (s, 1H), 7.0 (m, 4H),7.33 (m, 3H), 7.54 (m, 2H) mp 270–295° C. (dec); Anal calcd forC₂₄H₂₇CIN₂O; C=72.99, H=6.89, N=7.10, Cl=8.98; found C=72.91, H=6.91,N=7.15, Cl=8.98; [α]_(D) −102.22° (c=0.68, MeOH).

Example 20 3β-(4-Iodophenyl)-2β-(3-phenylisoxazol-5-yl)tropaneHydrochloride (RTI-181)

Reaction of 0.73 g (1.9 mmol) of3β-(4-Iodophenyl)-2β-(carbomethoxy)tropane as described above forRTI-181 gave after workup 1.46 g of crude isoxazole. Purification of thecrude by flash column chromatography [20% (ether/triethylamine 9:1) inhexane] gave 0.5 g (56%) of pure isoxazole RTI-181 which was furtherpurified by crystallizing from methylene chloride/hexane: ¹H NMR (CDCl₃)δ 1.72 (m, 3H), 2.15 (m, 2H), 2.28 (s, 3H), 3.22 (m, 2H), 3.35 (m, 2H),6.74 (m, 2H), 6.79 (s, 1H), 7.44 (m, 5H), 7.75 (m, 2H); IR (CHCl₃) 2940,1580, 1480, 1475, 1450, 1400, 1355, 1005 cm⁻¹

The isoxazole was crystallized as the hydrochloride salt: 1H NMR (MeOD)δ 2.54 (m, 6H), 2.92 (s, 3H), 3.79 (m, 1H), 4.05 (m, 1H), 4.19 (m, 1H),4.33 (m, 1H), 6.18 (s, 1H), 7.02 (m, 2H), 7.43 (m, 3H), 7.63 (m, 4H);mp>267° C. (dec); Anal calcd for C₂₃H₂₄ClIN₂O.0.5H₂O C=53.55, H=4.89,N=5.43, Cl=13.75; I=49.21: found C=53.75, H=4.87, N=5.41, Cl=13.68;I=48.95; [α]_(D) −91.11° (c=0.43, MeOH)

Example 21 Biochemistry of 3β-(Substitutedphenyl)-2β-(heterocyclic)tropanes

Inhibition of radioligand binding data at the dopamine, serotonin, andnorepinephrine transporters are listed in Table II, III and IV.

TABLE II 3β-(Substituted phenyl)-2β-(heterocyclic)tropanes

A IC₅₀ (nM) Code DA NE 5-HT NE/DA 5-HT/DA Name Het X [³H]-WIN 35, 428[³H]-nisoxetine [³H]-paroxetine Ratio Ratio RTI-163RTI-157

ClCH₃ 911 ± 6.1 1557 ± 196  17,386 ± 2050 32,478 ± 2078  5456 ±64 43,574 ± 5420  1921  628 RTI-165RTI-171RTI-180

ClCH₃I 0.59 ± 0.040.93 ± 0.090.73 ± 0.04 181 ± 12254 ± 31 67.9 ± 5.25572 ± 583818 ± 34636.4 ± 5.0 307 273 93 970 4105 498 RTI-177RTI-176RTI-181

ClCH₃I 1.28 ± 0.181.58 ± 0.022.57 ± 0.14 504 ± 29398 ± 18868 ± 95 2418 ±1365110 ± 187 100 ± 9.0 393 251 337  1889 3234 39 RTI-189RTI-178

ClCH₃ 19.7 ± 1.9835.4 ± 1.74 496 ± 42677 ± 68 1116 ± 1071699 ± 167 25195748 RTI-188RTI-195

ClCH₃ 12.6 ± 1.0347.5 ± 4.76 929 ± 881310 ± 37  3304 ± 19623,310 ± 822  7328 262 491  RTI-194

CH₃ 4.45 ± 0.12 253 ± 19 4885 ± 155 57 1098  RTI-200RTI-199

ClCH₃ 15.3 ± 2.4335.9 ± 3.4  4142 ± 46624,321 ± 3822  18,417 ±1509 51,460 ± 4513  271 677  1203 1434  RTI-202

Cl 1.37 ± 0.14 403 ± 30 1119 ± 120 294  817  RTI-219

Cl 5.71 ± 0.36 8563 ± 824 10,342 ± 76   1500  1811 

TABLE III Comparison of Transporter Binding Potencies

IC₅₀ (nM) RTI 5-HT DA NE No. R₁ R₂ [³H]Paroxetine [³H]WIN 35, 428[³H]Nisoxetine 279 CH₃ CH₃ 1.06 ± 0.39  5.98 ± 0.48 74.3 ± 3.8 353 C₂H₅CH₃ 0.69 ± 0.07 331 ± 17  148 ± 9.2 Par- 0.28 ± 0.02 623 ± 25 313 oxe-tine* 5-HT = serotonin DA = dopamine NE = norepinephrine *Aropax:Seroxat; see Merck Index.

TABLE IV 3β-(Substituted phenyl)-2β-(substituted)tropanes

IC₅₀ (nM) Code DA NE 5-HT Name R X [³H]-WIN 35, 428 [³H]-nisoxetine[³H]-paroxetine RTI-93 CH₂OH Cl  1.53 ± 0.15  43.8 ± 8.4   204 ± 16RTI-99 CH₂OH Br  1.49 ± 0.05   51 ± 4.6 RTI-100 CH₂OH F   47 ± 4.6  4741± 335 RTI-101 CH₂OH I  2.2 ± 0.19   26 ± 3.2 RTI-102 CO₂H I   474 ± 5743,400 ± 5500  1928 ± 120 RTI-103 CO₂H Br   278 ± 43 17,400 ± 1400  3070± 208 RTI-104 CO₂H F  2744 ± 141 >100,000 >100,00 RTI-105 CH₂OAc Cl 1.60 ± 0.05   127 ± 5.9   143 ± 25 RTI-108 CH₂Cl Cl  2.64 ± 0.31   129± 15   98 ± 8.7 RTI-123 CH₂OCOC₆H₅ Cl  1.78 ± 0.09   393 ± 30  3.53 ±0.58 RTI-131 CH₂NH₂ CH₃  10.5 ± 1.7   120 ± 20   855 ± 52 RTI-132CH₂N(CH₃)₂ CH₃  3.48 ± 0.11   137 ± 11   208 ± 18 RTI-139 CH₃ Cl  1.67 ±0.13    57 ± 2.6   85 ± 9.3 RTI-145 CH₂OCO₂CH₃ Cl  9.6 ± 0.42   1478 ±96  2930 ± 181 RTI-158 CN CH₃   57 ± 7.3   1624 ± 136  5095 ± 315RTI-161 CN Cl  13.1 ± 0.76   2516 ± 253  1887 ± 134 RTI-164 CH₂NHCH₃ CH₃ 13.8 ± 2.03   280 ± 19  2246 ± 94 RTI-230 —C(CH₃)═CH₂ Cl  1.28 ± 0.17  141 ± 16   57 ± 5.0 RTI-239 CH(CH₃)₂ CH₃  0.61 ± 0.07  35.6 ± 2.57  114 ± 3.69 RTI-240 CH(CH₃)₂ Cl  1.38 ± 0.03  84.5 ± 3.09  38.4 ± 2.31RTI-241 CH₂CO₂CH₃ CH₃  1.02 ± 0.06   124 ± 3.56   618 ± 28

This invention has been described in both generic terms, and byreference to specific description. No specific description or example isconsidered binding, unless so identified. Alternate forms and methodswill occur to those of ordinary skill in the art, without the exerciseof inventive faculty, and remain within the scope of this invention,save as limited by the claims set forth below.

1. A 2β,3β substituted compound of the formula:

wherein R₁ is hydrogen or C₁₋₅ alkyl, X is H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, C₁₋₄ alkoxy, C₂₋₆ alkynyl, halogen, amino, or acylamido, Zis H, I, Br, Cl, F, CN, CF₃, NO₂, N₃, OR₁, CONH₂, CO₂R₁, C₁₋₆ alkyl,NR₄R₅, NHCOR₅, or NHCO₂R₆, R₄ is C₁₋₆ alkyl, R₅ is C₁₋₆ alkyl, R₆ isC₁₋₆ alkyl, and R_(b) is C₁₋₆ alkyl, phenyl, or C₁₋₆ alkyl substitutedphenyl, or a pharmaceutically acceptable salt thereof.
 2. The compoundof claim 1, wherein R_(b) is CH₃ and X is Cl.
 3. The compound of claim2, wherein R₁ is CH₃ and Z is H.
 4. The compound of claim 1, whereinR_(b) is CH₃ and X is CH₃.
 5. The compound of claim 4, wherein R₁ is CH₃and Z is H.
 6. The compound of claim 1, wherein R_(b) is CH₃ and X is I.7. The compound of claim 6, wherein R₁ is CH₃ and Z is H.
 8. Thecompound of claim 1, wherein R_(b) is phenyl and X is Cl.
 9. Thecompound of claim 8, wherein R₁ is CH₃ and Z is H.
 10. The compound ofclaim 1, wherein R_(b) is phenyl and X is CH₃.
 11. The compound of claim10, wherein R₁ is CH₃ and Z is H.
 12. The compound of claim 1, whereinR_(b) is phenyl and X is I.
 13. The compound of claim 12, wherein R₁ isCH₃ and Z is H.
 14. The compound of claim 1, wherein R_(b) is4-chlorophenyl and X is 4-chloro.
 15. The compound of claim 14, whereinR₁ is CH₃ and Z is H.
 16. The compound of claim 1, wherein R_(b) is4-methoxyphenyl and X is 4-chloro.
 17. The compound of claim 16, whereinR₁ is CH₃ and Z is H.
 18. The compound of claim 1, wherein R_(b) is4-fluorophenyl and X is 4-chloro.
 19. The compound of claim 18, whereinR₁ is CH₃ and Z is H.
 20. The compound of claim 1, wherein R_(b) isethyl and X is 4-chloro.
 21. The compound of claim 20, wherein R₁ is CH₃and Z is H.
 22. The compound of claim 1, wherein R_(b) is CH(CH₃)₂ and Xis 4-chloro.
 23. The compound of claim 22, wherein R₁ is CH₃ and Z is H.24. The compound of claim 1, wherein R_(b) is C(CH₃)₃ and X is 4-chloro.25. The compound of claim 24, wherein R₁ is CH₃ and Z is H.
 26. Thecompound of claim 1, which is said pharmaceutically acceptable salt. 27.A pharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.